Abstract: Oxytocin (OT) is a neuropeptide synthesized in the magnocellular cells of the hypothalamic paraventricular and supraoptic nuclei. Previous studies have found that OT plays an important role in modulating social cognition and emotional processing. A systematic review of the modulatory effects of OT on cognitive behavior can not only deepen our understanding of the mechanism underlying OT's effects on learning and memory but can also serve to motivate and guide future studies in this important field. The present systematic review details of studies using different methodologies to investigate the specific regulatory effects of OT on learning and memory and its underlying neural mechanisms in both animal models and humans. These studies demonstrate firstly that the effects of OT on animal learning are highly complex, with OT promoting either facilitatory or inhibitory effects dependent upon injection locations (e.g., hippocampal dentate gyrus vs. dorsal raphe nucleus), doses, and types of learning (passive avoidance vs. spatial learning). In human studies, OT is primarily administered intranasally (usually as a 24 IU dose) in order to modulate learning and its effects are mainly dependent upon the type of learning involved. Significant effects of OT have been demonstrated in social learning, fear conditioning, and extinction, perhaps by regulating the functional state of core hubs in emotional processing and learning networks, including the amygdala and hippocampus. On the other hand, no significant effects of OT have been found in the context of learning involving monetary rewards. Secondly, studies in animal models have reported that the effects of OT on memory are mainly dose-dependent, with intracerebroventricular injections at low-doses facilitating memory performance while high-doses have an inhibitory effect. In human studies, significant modulatory effects of OT have mainly been found for the memory of social stimuli, particularly for emotional faces. These studies have shown that whether a facilitatory or inhibitory effect is observed is dependent upon when OT is administered (before vs. after memory encoding), test intervals, stimuli used (e.g., valences and types), etc. These effects of OT may act via the binding of externally administered OT to OT receptors extensively distributed in key learning and memory brain networks including the dopamine reward pathway and limbic system (specifically the amygdala and hippocampus). In summary, although OT has an important modulatory effect on learning and memory, this is highly complex, with either facilitatory or inhibitory effects being reported dependent upon experimental paradigms, stimulus materials, locations and time points of administration, and doses used. In order to overcome current limitations in this field, it is necessary for future studies to combine the respective methodological advantages of animal models with human studies and to standardize experimental protocols and treatment procedures. Further research is also required to explore the therapeutic potential of OT for learning and memory dysfunction in psychiatric disorders.

Key words: oxytocin, learning, memory, neural mechanism